Pure Reference Research Articles

Liquid chromatography–mass spectrometry behavior of Girard's reagent T derivatives of oxosteroid intact phase II metabolites for doping control purposes

Intact phase II steroid metabolites have poor product ion mass spectra under collision-induced dissociation (CID) conditions. Therefore, we present herein the liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/(MS)) behavior of intact phase II metabolites of oxosteroids after derivatization. Based on the fact that Girard's reagent T (GRT), as derivatization reagent, was both convenient and efficient in terms of the enhancement in the ionization efficiency and the production of diagnostic product ions related to the steroid moiety, the latter was preferably selected between methoxamine and hydroxylamine upon the model compounds of androsterone glucuronide and androsterone sulfate. Sixteen different glucuronides and 29 sulfate conjugated metabolites of anabolic androgenic steroids (AASs), available either as pure reference materials or synthesized/extracted from administration studies, were derivatized with GRT, and their product ion spectra are presented. Product ion spectra include in all cases high number of product ions that in some cases are characteristic for certain structures of the steroid backbone. More specifically, preliminary results have shown major differences in fragmentation pattern for 17α/17β-isomers of the sulfate conjugates, but limited differentiation for 17α/17β-isomers of glucuronide conjugates and for 3α/3β- and 5α/5β-stereoisomers of both sulfate and glucuronide conjugates. Further to the suggestion of the current work, application on mesterolone administration studies confirmed-according to the World Anti-Doping Agency (WADA) TD2015IDCR-the presence of seven intact phase II metabolites, one glucuronide and six sulfates with use of LC-ESI-MS/(MS).

Novel suspension route to incorporate graphene nano-platelets in HVAF-sprayed Cr3C2–NiCr coatings for superior wear performance

Graphene nano platelets (GNP) have several attractive properties, including excellent lubricity that can be used to develop wear-resistant coatings. Thermally sprayed chromium carbideenickel chromium (Cr3C2eNiCr) coatings are widely employed to impart wear resistance to engineering components. This work attempts to improve the wear resistance of high velocity air fuel (HVAF) sprayed Cr3C2eNiCr coatings by incorporating GNP using a hybrid approach in which Cr3C2eNiCr (powder) and GNP (suspension) are co-axially injected. Two different powder-to-suspension delivery ratios were employed in this study that utilizes a liquid feedstock in tandem with a HVAF system. Furthermore, for comparison, a pure (without graphene) Cr3C2eNiCr reference coating was deposited by the HVAF process using identical spray parameters. The as-sprayed coatings were characterized for their microstructure and phase constitution by SEM/EDS and X-Ray Diffraction. Mechanical properties such as hardness and fracture toughness were evaluated using micro-indentation technique. The hybrid coatings were subjected to dry sliding wear tests and wear performance was compared with reference Cr3C2eNiCr. The GNP incorporated hybrid coatings exhibited lower CoF and lower wear rates than the reference Cr3C2eNiCr coating. Post wear SEM/EDS analysis revealed different wear mechanisms predominant in the investigated coatings. Utilizing the above as a case study, this work provides key insights into a new approach to produce GNP incorporated coatings for mitigating wear.

Mass Balance Method for Si-Traceable Purity Assignment of Synthetic Oxytocin

Oxytocin is not only a significant peptide drug for enhancing uterine contractions, but also an emerging biomarker and therapeutic target of mental disorders in clinical practice. There is a pressing need for the standardization of OXT assays because of its low pharmaceutical quality and large variations among measurement approaches. SI-traceable analytical methods and well-characterized pure reference materials are urgently needed to set up standard reference measurement systems in laboratory medicine, ensuring the accuracy and comparability of test results during the manufacture, clinical diagnosis and treatment. Herein, the purity assignment of a synthetic oxytocin containing a disulfide linkage was established based on a mass balance method, which had never been performed for a cross-linked peptide. An in-house validated liquid chromatography-high-resolution tandem mass spectrometry method was developed for the determination of structurally-related impurities in the study material. 21 structurally-related impurities including deamidations, oxidations, and amino acid insertions, etc. ranging from 0.05 mg g-1 to 15.65 mg g-1 were identified and quantified by applying a hierarchy calibration concept. This study subsequently discusses a fit for purpose assessment for non-peptide related impurities including water, non-volatile counterions, inorganic elements, and volatile organic compounds that were determined using coulometric Karl Fischer titration, ion chromatography, inductively coupled plasma mass spectrometry, and headspace gas chromatography-mass spectrometry, respectively. The resulting assigned value (796.5 mg g-1) is determined to be traceable to SI units associated with a small measurement uncertainty of 6.5 mg g-1 (k= 2). The method developed in this study has been verified through an international key comparison jointly coordinated by the Bureau International des Poids et Mesures and the National Institute of Metrology.

Measurement of Free Testosterone in Serum Using Equilibrium DialysisCoupled With ID-UHPLC-MS/MS: Comparison Between Equilibrium Devices

Free testosterone (FT) has been used as a biomarker in clinical patient care and public health research to assess and manage patients with androgenic abnormalities. The latest Endocrine Society clinical practice guideline for testosterone therapy in men with hypogonadism recommends measuring FT for those with borderline and low total testosterone concentrations, or those who have conditions that change SHBG concentrations, such as some metabolic or hormonal diseases, certain medication use, or SHBG genetic polymorphisms. Measuring FT is technically challenging and shows high variability. The CDC clinical standardization program is developing a high throughput method using the gold-standard equilibrium dialysis (ED) procedure with isotope dilution ultra-high-performance liquid chromatography tandem mass spectrometry (ID-UHPLC-MS/MS).A serum sample was dialyzed against a protein-free HEPES buffer (pH 7.4) at 37 °C until equilibrium. After isolating endogenous FT from protein-bound testosterone by ED, isotope-labeled internal standard (13C3-testosterone) was added to the dialysate for quantification. Certified pure primary reference material (National Measurement Institute M914) was used to prepare calibrators, enabling traceable quantitation and ensuring measurement trueness. FT was further isolated from the dialysate matrix using supported liquid extraction and a chromatographic separation from interfering compounds and quantitation by tandem MS. The dialysis step requires maintaining the endogenous free hormone equilibrium so that results in dialysate reflect FT concentrations in the blood without influence from dilution, temperature, or pH. The dialyzer system has a 1:1 sample-to-buffer volume and has been used in reference measurement procedures for free hormone measurements, serving as the standard for method performance comparison. Four commercially available devices designed for high throughput in a multiple well-plate format, requiring respective sample-to-buffer ratios, were evaluated for their recovery, speed, ease of automation by a liquid handling system, repeatability, and robustness. Preliminary results showed that a device with 1:1 sample-to-buffer volume had the most comparable results to those obtained from the standard dialyzer, with the mean bias less than 15%. The device with the highest sample-to-buffer ratio showed bias as high as 50%. These data suggest that controlling sample-to-buffer ratio is a critical step in ED FT method.

Removal of Cu2+, Fe2+, Ni2+, Zn2+ and Cl− from Industrial wastewater using a Polyethersulfone/Carbon Nanotube/Polyvinyl alcohol composite membrane

Polyethersulfone (PES) is commonly used to fabricate ultrafiltration (UF) membranes applied during the treatment of wastewater due to its high permeability and tensile properties, chemical and thermal stability. However, PES has low hydrophilicity due the sulfonyl functional group and therefore becomes susceptible to fouling, resulting in reduced membrane performance and lifespan. In this study, 10 wt% PES/CNT membranes were prepared by infusing 2.5, 5, 7.5 and 10 wt% Carbon nanotubes (CNTs) into PES to produce PES/2.5 wt% CNT, PES/5 wt% CNT, PES/7.5 wt% CNT and PES/10 wt% CNT membranes by phase inversion. The membranes were immersed in 1 wt% PVA solution to coat a hydrophilic PVA layer on the surface of the membranes to fabricate PES/2.5 wt% CNT/PVA, PES/5 wt% CNT/PVA, PES/7.5 wt% CNT/PVA and PES/10 wt% CNT/PVA membranes. A 10 wt% pure PES reference membrane was also prepared for comparison purposes. This research focused on evaluating the effect of coating a PVA layer on the performance of a PES/CNT/PVA membrane. TEM characterization revealed that the CNTs are MWCNT, PSD was done to obtain CNT particle size, FTIR confirmed the formation of –COOH and –OH functional groups on the surface of CNTs, SEM confirmed porous membrane structures, BET showed an increase in pore size at higher CNTs loading, tensile properties showed a decrease when CNTs were added, and contact angle studies showed significant increase in hydrophilicity with the addition of CNTs and PVA. Filtration experiments were conducted using a dead-end stirred cell. PES/7.5 wt% CNT/PVA showed the most improved results with a good trade-off balance between membrane flux and rejection, generating a flux of 7.94 L/m2h and rejection of 88.56% Cu2+, 96.15% Fe2+, 89.06% Ni2+, 100% Zn2+ and 99.93% Cl−. Anti-fouling tests for PES/7.5 wt% CNT/PVA conducted using a cross-flow filtration rig showed that only 70.77% of the flux could be recovered. These results showed that a PES membrane that has been infused with functionalized CNTs and coated with a layer of PVA membrane can effectively remove Cu2+, Fe2+, Ni2+, Zn2+ and Cl− from industrial wastewater.

Industrially Purified Nd Materials Identified by Distinct Mass-Dependent Isotopic Composition

Rare earth elements (REEs) are considered emerging anthropogenic pollutants. Anthropogenic lanthanum, cerium, samarium, and gadolinium alone, or excess of all the REEs have already been reported in the environment. In addition, it is only a matter of time for neodymium (Nd) of anthropogenic origin to be reported disseminated in the environment, given its growing demand for new technologies and its use in permanent magnets of wind turbine. So far, only in a few cases was the addition of anthropogenic Nd detected in soils and sediments by the measurements of REE concentrations. For this reason, we propose to use the Nd isotopic composition to help the distinction of pollution. The isotopic tracing of Nd using variations in the abundance of 143Nd from the radioactive decay of 147Sm (Nd-radiogenic composition) is one option. Here, we expand the Nd isotopic fingerprinting by the investigation of the stable Nd isotopic composition expressed as δxNd, the relative permil (%0) deviation from the isotopic composition of the pure Nd JNdi-1 reference standard. The measurement of δxNd used a MC-ICPMS (multi-collector inductively coupled plasma mass spectrometry) with sample-standard bracketing technique, allowing the determination of precise and accurate Nd isotopic variations. Our results show that Nd-magnets (Neo) and man-made purified Nd materials are not significantly different on average (respectively, δ148Nd of −0.105 ± 0.023 and −0.120 ± 0.141%0). More importantly, they are different from terrestrial rocks (δ148Nd of −0.051 ± 0.031%0). Moreover, the Nd-radiogenic composition of Neo can be highly variable, even when they come from a single supplier. In addition, the study of all Nd stable isotopic compositions demonstrates that irrespective of their natural origin (witnessed by their Nd-radiogenic composition), all Nd from rocks and man-made materials are related by mass-dependent isotopic fractionation laws. We also have defined a parameter, the Δ148−150Nd′, allowing the distinction of thermodynamic isotopic fractionation (the Δ148−150Nd′ is invariant) from kinetic isotopic fractionation (the Δ148−150Nd′ is negatively correlated with the δ148Nd). Such covariation is observed for anthropogenic materials that could be seen as small deficit in 150Nd (around 5 ppm/%0/amu), but too small to be consistent with nuclear field effect. On the other hand, the anthropogenic material defines a covariation in the Δ148−150Nd'–δ148Nd space in full agreement with the theoretical expectation from mass-dependent kinetic isotopic fractionation. The mass-dependent fractionation of Nd by chromatographic separation is also consistent with a kinetic isotopic fractionation. The purification of Nd from other light REEs by industrial processes involves chromatographic separation and, therefore, is likely to produce anthropogenic Nd with low values for δ148Nd associated with high values for Δ148−150Nd′. Both are resolvable with current MC-ICPMS technology and could be useful to trace incoming anthropogenic pollution in the environment. In soils, the combination of low values for δ148Nd with high values for Δ148−150Nd′ is likely to be an unambiguous pollution signal from the degradation in the environment of Neo or other industrial products, especially if this is associated with an Nd-radiogenic composition inconsistent with the surrounding rocks and soils. In contrast, the industrial residue of Nd purification could be characterized by high δ148Nd with low values for Δ148−150Nd′, and the leak or the discharge of such residue could also be unambiguously distinguished.

Exploring the relationship between the faithfulness and entanglement of two qubits

A conceptually simple and experimentally prevalent class of entanglement witnesses, known as fidelity witnesses, detects entanglement via a state's fidelity with a pure reference state. While existence proofs guarantee that a suitable witness can be constructed for every entangled state, such assurances do not apply to fidelity witnesses. Recent results have found that entangled states that cannot be detected by a fidelity witness, known as unfaithful states, are exceedingly common among bipartite states. In this paper, we show that even among two-qubit states, which are the simplest of all entangled states, unfaithful states can be created through a suitable application of decoherence and filtering to a Bell state. We also show that the faithfulness is not monotonic to entanglement, as measured by the concurrence. Finally, we experimentally verify our predictions using polarization-entangled photons, and specifically we demonstrate a situation in which an unfaithful state is brought to faithfulness at the expense of further reducing the entanglement of the state.

Fast & fluorinated – Development and validation of a rapid benchtop NMR approach and other routine screening methods for the detection and quantification of synthesized fluorofentanyl derivatives

Fluorinated fentanyl regioisomers have become increasingly common in forensic casework. This study reports the synthesis of eight fluorinated fentanyl derivatives as pure reference materials and their complete NMR, infrared and mass spectral characterisation. Presumptive colour tests and TLC results are presented as an initial screening method for these compounds. The fully validated GC–MS method (employing SIM mode) allows the quantification of the target analytes (LOD = 9–20 ng/mL, LOQ = 31–67 ng/mL), fentanyl, heroin, acetaminophen and caffeine, within 13 min. In most cases, the regioisomeric fluorofentanyls were resolved from each other except for the 3′- and 4′-fluorinated derivatives (5b and 5c). To achieve full separation, an orthogonal benchtop 19F NMR method allows the identification and quantification of target analogues (LOD = 74–400 μg/mL, LOQ = 290–1340 μg/mL). The 19F NMR method allows the detection of fluorinated fentanyl analogues at a low concentration (2.4%w/w) in heroin.

Automated Full-Pattern Summation of X-Ray Powder Diffraction Data for High-Throughput Quantification of Clay-Bearing Mixtures

AbstractX-ray powder diffraction (XRPD) is found consistently to be the most accurate analytical technique for quantitative analysis of clay-bearing mixtures based on results from round-robin competitions such as the Reynolds Cup (RC). A range of computationally intensive approaches can be used to quantify phase concentrations from XRPD data, of which the ‘full-pattern summation of prior measured standards’ (FPS) has proven accurate and parsimonious. Despite its proven utility, the approach often requires time-consuming selection of appropriate pure reference patterns to use for a given sample. As such, applying FPS to large and mineralogically diverse datasets is challenging. In the present work, the accuracy of an automated FPS algorithm implemented within the powdR package for the R Language and Environment for Statistical Computing was tested on a set of 27 samples from nine RC contests. The samples represent challenging and diverse clay-bearing mixtures with known concentrations, with the added advantage of allowing the accuracy of the algorithm to be compared with results submitted to previous contests. When supplied with a library of 201 reference patterns representing a comprehensive range of phases that may be encountered in natural clay-bearing mixtures, the algorithm selected appropriate phases and achieved a mean absolute bias of 0.57% for non-clay minerals (n = 275), 2.37% for clay minerals (n = 120), and 4.43% for amorphous phases (n = 14). This accuracy would be sufficient for top-3 placings in all nine RC contests held to date (RC1 = 2nd, RC2 = 2nd, RC3 = 1st; RC4 = 2nd; RC5 = 1st; RC6 = 3rd; RC7 = 3rd; RC8 = 1st; RC9 = 2nd). The comparatively low values of absolute bias in combination with the competitive placings in all RC contests tested is particularly promising for the future of automated quantitative phase analyses by XRPD.

Local slip resistances in equal-molar MoNbTi multi-principal element alloy

In this work, we calculate the local slip resistances (LSRs) in equal-molar MoNbTi multi-principal element alloy via molecular static simulations. We consider dislocations of either screw or edge character gliding on four types of slip planes, {110}, {112}, {123}, and {134}, in either forward or backward sense of the 111 slip direction. As references, we also compute the Peierls stresses of the same dislocations in two natural reference metals, Mo and Nb, and a synthetic one, the mean-field, A-atom potential-based MoNbTi. Further, we compare the LSRs with the corresponding ideal shear strengths that do not account for the lattice distortions induced by dislocation cores. We show that for neither dislocation character is the LSR on the {110} plane the lowest in MoNbTi, in contrast to Mo and Nb. For edge dislocations, slip on the {134} plane is the easiest, but for the screw dislocations, it is the hardest. For screw dislocations, the {112} glide plane is the most favored, while for edge dislocations, it is the least favored. We also find that the screw-to-edge ratio in the slip resistance is reduced by one order of magnitude in MoNbTi compared to that of any pure reference metal for the same type of slip plane. These results suggest that, in contrast to pure body-centered cubic (BCC) metals, BCC MPEAs could deform by a multiplicity of slip modes due to the lower screw-to-edge ratios and the lower LSRs for edge dislocations on the three higher order planes.

Compostable, fully biobased foams using PLA and micro cellulose for zero energy buildings

Ecological, health and environmental concerns are driving the need for bio-resourced foams for the building industry. In this paper, we examine foams made from polylactic acid (PLA) and micro cellulose fibrils (MCF). To ensure no volatile organic compounds in the foam, supercritical CO2 (sc-CO2) physical foaming of melt mixed systems was conducted. Mechanical and thermal conductivity properties were determined and applied to a net zero energy model house. The results showed that MCF had a concentration dependent impact on the foams. First structurally, the presence of MCF led to an initial increase followed by a decrease of open porosity, higher bulk density, lower expansion ratios and cell size. Differential Scanning Calorimetry and Scanning Electron Microscopy revealed that MCF decreased the glass transition of PLA allowing for a decrease in cell wall thickness when MCF was added. The mechanical performance initially increased with MCF and then decreased. This trend was mimicked by thermal insulation which initially improved. Biodegradation tests showed that the presence of cellulose in PLA improved the compostability of the foams. A maximum comparative mineralization of 95% was obtained for the PLA foam with 3 wt.% MCF when expressed as a fractional percentage of the pure cellulose reference. Energy simulations run on a model house showed that relative to an insulation of polyurethane, the bio-resourced foams led to no more than a 12% increase in heating and cooling. The energy efficiency of the foams was best at low MCF fractions.

Validation of XRD phase quantification using semi-synthetic data

Validating phase quantification procedures of powder X-ray diffraction (XRD) data for an implementation in an ISO/IEC 17025 accredited environment has been challenging due to a general lack of suitable certified reference materials. The preparation of highly pure and crystalline reference materials and mixtures thereof may exceed the costs for a profitable and justifiable implementation. This study presents a method for the validation of XRD phase quantifications based on semi-synthetic datasets that reduces the effort for a full method validation drastically. Datasets of nearly pure reference substances are stripped of impurity signals and rescaled to 100% crystallinity, thus eliminating the need for the preparation of ultra-pure and -crystalline materials. The processed datasets are then combined numerically while preserving all sample- and instrument-characteristic features of the peak profile, thereby creating multi-phase diffraction patterns of precisely known composition. The number of compositions and repetitions is only limited by computational power and storage capacity. These datasets can be used as input files for the phase quantification procedure, in which statistical validation parameters such as precision, accuracy, linearity, and limits of detection and quantification can be determined from a statistically sound number of datasets and compositions.

Vaccinating SIS epidemics under evolving perception in heterogeneous networks.

Vaccination is an effective intervention against epidemics. Previous work has demonstrated that psychological cognition affects individual behavior. However, perceptual differences between individuals, as well as the dynamics of perceptual evolution, are not taken into account. In order to explore how these realistic characteristics of psychological cognition influence collective vaccination behavior, we propose a prospect theory based evolutionary vaccination game model, where the evolution of reference points is used to characterize changes in perception. We compare the fractions of vaccinated individuals and infected individuals under variable reference points with those under the expected utility theory and the fixed reference point, and highlight the role of evolving perception in promoting vaccination and contributing to epidemic control. We find that the epidemic size under variable reference point is always less than that under the expected utility theory. Finding that there exists a vaccination cost threshold for the cognitive effect, we develop a novel mixed-reference-point mechanism by combining individual psychological characteristics with network topological feature. The effectiveness of this mechanism in controlling the network epidemics is verified with numerical simulations. Compared with pure reference points, the mixed-reference-point mechanism can effectively reduce the final epidemic size, especially at a large vaccination cost.Graphical abstract

In Vitro Inhibition of Phosphodiesterase 3B (PDE 3B) by Anthocyanin-Rich Fruit Juice Extracts and Selected Anthocyanins.

Phosphodiesterases (PDEs) are essential enzymes for the regulation of pathways mediated by cyclic adenosine monophosphate (cAMP). Secondary plant compounds like anthocyanins (ACs) can inhibit PDE activity and, consequently, may be beneficial for lipid metabolism. This study investigated 18 AC-rich juice extracts and pure reference compounds from red fruits for potential inhibitory effects on PDE 3B activity. Extracts were obtained through adsorption on Amberlite® XAD 7 resin. Based on this screening, the chokeberry, blueberry, pomegranate, and cranberry extracts were active, with half maximal inhibitory concentrations (IC50) ranging from 163 ± 3 µg/mL to 180 ± 3 µg/mL. The ACs in these extracts, peonidin-3-glucoside and cyanidin-3-arabinoside, were the most active single compounds (IC50 = 56 ± 20 µg/mL, 108 ± 6 µg/mL). All extracts comprised high amounts of phenolic compounds, as determined by the Folin–Ciocalteu assay, ranging from 39.8 ± 1.5 to 73.5 ± 4.8 g gallic acid equivalents (GAE)/100 g extract. Pomegranate and chokeberry extracts exhibited the largest amounts of polyphenols (72.3 ± 0.7 g GAE/100 g, 70.6 ± 4.1 g GAE/100 g, respectively). Overall, our results showed that fruit juice extracts and their ACs can inhibit PDE activity. Any potential health benefits in vivo will be investigated in the future.

Comparative pharmacokinetics of Ding-Zhi-Xiao-Wan preparation and its single herbs in rats by using a putative multiple-reaction monitoring UPLC-MS/MS method.

The formula of Chinese medicine, Ding-Zhi-Xiao-Wan (DZXW), has the distinct feature of compatibility therapy, which is attributed to the interactions of multi-herbs. However, the quantification problem caused by the absence of pure reference standards is a bottleneck to clarify the compatibility advantages from the perspective of pharmacokinetics (PKs). This study aimed to develop a putative multiple-reaction monitor (PMRM) strategy for exploring the comparative PKs of DZXW and its single herbs. First, precursor ion and tandem mass spectrometry (MS/MS) chromatograms were obtained via ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight MS (UHPLC-Q-TOF-MS) under different collision energy (CE) values. Then, the two most abundance ions in the MS/MS chromatograms were chosen as product ions, and CE values were selected according to the abundance of the product ion peaks. Next, a PMRM strategy consisting of optimal MRM parameters was constructed. Finally, the established PMRM parameters were imported to UHPLC coupled with triple quadrupole MS (UHPLC-TQ-MS) for quantification. The strategy was exemplified by the comparative PK study of DZXW and its single herbs. This strategy could extend the PK scopes of multi-components. The quantitative results displayed substantial variations in PK parameters between DZXW and its single herbs. The PK parameters indicated that the DZXW formula could increase the exposure levels of most ingredients and reduce the maximum concentration (Cmax ) of Radix Polygala, indicating that herb compatibility could produce synergistic effects and diminish possible toxic effects. This study provides a viable orientation for the compatibility investigation of traditional Chinese medicine.

Metabolic perturbations prior to hepatocellular carcinoma diagnosis: Findings from a prospective observational cohort study.

Hepatocellular carcinoma (HCC) development entails changes in liver metabolism. Current knowledge on metabolic perturbations in HCC is derived mostly from case-control designs, with sparse information from prospective cohorts. Our objective was to apply comprehensive metabolite profiling to detect metabolites whose serum concentrations are associated with HCC development, using biological samples from within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (>520 000 participants), where we identified 129 HCC cases matched 1:1 to controls. We conducted high-resolution untargeted liquid chromatography-mass spectrometry-based metabolomics on serum samples collected at recruitment prior to cancer diagnosis. Multivariable conditional logistic regression was applied controlling for dietary habits, alcohol consumption, smoking, body size, hepatitis infection and liver dysfunction. Corrections for multiple comparisons were applied. Of 9206 molecular features detected, 220 discriminated HCC cases from controls. Detailed feature annotation revealed 92 metabolites associated with HCC risk, of which 14 were unambiguously identified using pure reference standards. Positive HCC-risk associations were observed for N1-acetylspermidine, isatin, p-hydroxyphenyllactic acid, tyrosine, sphingosine, l,l-cyclo(leucylprolyl), glycochenodeoxycholic acid, glycocholic acid and 7-methylguanine. Inverse risk associations were observed for retinol, dehydroepiandrosterone sulfate, glycerophosphocholine, γ-carboxyethyl hydroxychroman and creatine. Discernible differences for these metabolites were observed between cases and controls up to 10 years prior to diagnosis. Our observations highlight the diversity of metabolic perturbations involved in HCC development and replicate previous observations (metabolism of bile acids, amino acids and phospholipids) made in Asian and Scandinavian populations. These findings emphasize the role of metabolic pathways associated with steroid metabolism and immunity and specific dietary and environmental exposures in HCC development.

Component Quantification in Solids with the Mixture Analysis Using References Method.

Quantifying components in solid mixtures composed of the same chemical species exhibiting different physical forms represents a difficult challenge in many areas of chemistry. The development of small-molecule active pharmaceutical ingredients (APIs) is a classic example. APIs predominantly exhibit polymorphism and the propensity to form solvates and hydrates. The various API phases typically display different physical properties affecting chemical stability, processability, and bioperformance. Accordingly, API development critically relies on characterizing and quantifying the relevant API forms in complex mixtures in the presence of each other and in the presence of excipients. Presented here is a new solid-state-NMR-based quantification method for components in solid mixtures: mixture analysis using references (MAR). The method utilizes weighted pure component reference spectra in a linear combination fitting procedure to reproduce the corresponding mixture spectrum. The results yield the respective component contributions to the mixture composition. Using several model systems of varying complexity, the applicability and performance of the MAR analysis utilizing 13C and 19F cross-polarization magic-angle-spinning data are evaluated. Finally, the MAR method is compared to one of the most commonly applied traditional quantification methods. The results demonstrate that MAR performs with the same high accuracy as conventional methods. However, MAR exhibits clear efficiency advantages over conventional methods by requiring significantly less overall time (experimental and computational) and displaying remarkable robustness and general applicability. The MAR quantification protocol as presented here can easily be applied to nonpharmaceutical molecular systems in other branches of chemistry.

Direct co-deposition of mono-sized nanoparticles during sputtering

Nanoparticle-reinforced thin films synthesis is often limited by precipitation thermodynamics and kinetics to certain material combinations and nanoparticle size distributions. We demonstrate a new method that allows direct co-deposition of mono-sized nanoparticles with various matrix materials, independent particle size and composition control, yielding flexible material selection, and nanoparticle density spatial variations laterally and depth-wise. Tungsten nanoparticles were co-deposited into magnetron-sputtered copper, giving a uniform distribution of nanoparticles in transmission electron microscopy. To demonstrate the application potential, W nanoparticles stabilized nanograined Cu at 500 °C; pure Cu reference showed significant grain growth. This method opens new possibilities in tailored nanocomposite fabrication.

Mapping urban-rural gradients of settlements and vegetation at national scale using Sentinel-2 spectral-temporal metrics and regression-based unmixing with synthetic training data

The increasing impact of humans on land and ongoing global population growth requires an improved understanding of land cover (LC) and land use (LU) processes related to settlements. The heterogeneity of built-up areas and infrastructures as well as the importance of not only mapping, but also characterizing anthropogenic structures suggests using a sub-pixel mapping approach for analysing related LC from space. We implement a regression-based unmixing approach for mapping built-up surfaces and infrastructure, woody vegetation and non-woody vegetation for all of Germany and Austria at 10 m resolution to demonstrate the potential of sub-pixel mapping. We map LC fractions for one point in time, using all available Sentinel-2 data from 2017 and 2018 (<70% cloud cover). We combine the concept of synthetically mixed training data with statistical aggregations from spectral-temporal metrics (STM) derived from Sentinel-2 reflectance time series. We specifically examine how STM can be used for creating synthetically mixed training data. STM are known to facilitate large area mapping by being largely independent of image acquisition dates and inherently incorporate phenological information. Vegetation is an important part of settlements and time series information supports its mapping. Synthetically mixed training data facilitates a streamlined training by using pure reference spectra to generate artificial mixtures as input to regression modelling of LC fractions in mixed pixels. We here show how combining both offers great potential for wall-to-wall LC fraction mapping. We further investigate the positive effect of STM on map results by comparing the performance of different subsets of STM combinations. Our results indicate that many STM combinations containing spectral variability and vegetation indices provide suitable input to creating synthetic training data for regression-based fraction mapping. Results for built-up surfaces and infrastructure (MAE 0.13/RMSE 0.18 at 20 m resolution), woody vegetation (0.18, 0.22) and non-woody vegetation (0.14, 0.19) are highly consistent across Germany and Austria. Only a few surface types were not accurately predicted in our nation-wide mapping. Further research is required to optimize mapping of temporally invariant bare soil and rock surfaces that show spectral similarity to built-up surfaces and infrastructure. The proposed methodology combines benefits of both regression-based modelling with synthetically mixed training data and STM, and thus facilitates mapping of LC fractions on a national scale and at high resolution. Such information will allow to better characterize settlements and identifying processes such as densification that are best represented by continuous LC mapping.

A high-capacity graphene/mesocarbon microbead composite anode for lithium-ion batteries

The graphene/mesocarbon microbead (MCMB) composite is assessed as an anode material with a high capacity for lithium-ion batteries. The composite electrode exhibits improved cycling stability and rate capability, delivering a high initial charge/discharge capacity of 421.4 mA·h/g/494.8 mA·h/g as well as an excellent capacity retention over 500 cycles at a current density of 40 mA/g. At a higher current density of 800 mA/g, the electrode still retains 35% of its initial capacity which exceeds the capacity retention of pure graphene or MCMB reference electrodes. Cyclic voltammetry and electrochemical impedance spectroscopy reveal that the composite electrode favors electrochemical kinetics as compared with graphene and MCMB separately. Superior electrochemical properties suggest a strong synergetic effect between highly conductive graphene and MCMB.